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About
In this is a randomized phase II study the addition of hd-FMT (healthy donor fecal-microbiota transplant) to pembrolizumab /lenvatinib in PD-1 R/R melanoma will be evaluated over a 104-week period in patients with anti-PD-1 R/R disease. Patients with PD-1 refractory advanced melanoma are eligible to enroll, excluding patients with prior lenvatinib (or other TKI) exposure. Intestinal microbiome composition mediates response to anti-PD-1 by affecting systemic inflammatory tone.
Full description
Despite treatment advances, 40-60% of melanoma patients do not respond or fail to respond durably; and the management of relapsed/refractory (R/R) disease remains an important problem for the field. The importance of intact immune surveillance function in controlling outgrowth of neoplastic transformations has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma. Targeting TAMs (tumor associated macrophages, which are innate immune cells of heterogeneous origins that accumulate within the tumor microenvironment (TME) as tumors progress and interfere with antitumor T cell mediated responses) via targeted depletion, inhibition of active migration, and/or promotion of activation and differentiation have been pursued as therapeutic strategies to increase efficacy of ICI therapy clinically and preclinically. The pembrolizumab/lenvatinib combination has been explored in several clinical settings and been granted approval for two indications including advanced endometrial carcinoma and RCC. In addition to tumor-intrinsic mechanisms supporting resistance to anti-PD-1, the gut microbiome is a major tumor-extrinsic regulator of responses to anti-PD-1; In this trial, that will be in the form of hdFMT (healthy donor fecal-microbiota transplant).
Sex
Ages
Volunteers
Inclusion criteria
Patients with cutaneous melanoma or unknown primary melanoma may enroll. Patients with uveal or mucosal or acral-lentiginous melanoma are excluded.
Male participants:
• A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
Female participants:
Participants must have progressed on treatment with an anti-PD(L)1 ICI administered either as monotherapy or in combination with other checkpoint inhibitors or other standard/investigational therapies. PD-1 treatment progression is defined by meeting all the following criteria:
Patients with CNS disease are eligible if CNS metastases are treated and deemed stable prior to date of enrollment.
Prior treatment(s)
• NOTE: Prior anti-CTLA-4 ICI is allowed but not required.
• NOTE: Given the clear benefit of immunotherapy (over BRAF/MEK inhibitor therapy) in BRAFV600 mutant melanoma, BRAFV600 mutant patients need not have received BRAF/MEK inhibitor therapy prior to enrollment.
Willingness to repeatedly receive FMT administered endoscopically (colonoscopy or sigmoidoscopy) following necessary bowel preparation pre-procedure.
NOTE: Understands infectious risks associated with FMT administration.
o Although FMT infusate has been screened for bacteria, viruses, fungi and parasites there is a risk of transmission of known and unknown infectious organisms contained in the donor stool. Post-FMT bacteremia (e.g. E. coli), sepsis and fatal events may rarely occur.
NOTE: Understands non-infectious risks associated with FMT administration.
NOTE: Understand risks associated with endoscopy (colonoscopy or sigmoidoscopy) including risk of infection transmission, colonic perforation, aspiration pneumonia, and death.
NOTE: Understand that data regarding the long-term safety risk of FMT are lacking.
Presence of measurable disease based on RECIST 1.1.
Able to provide newly obtained core or excisional biopsy of a tumor lesion not previously irradiated to undergo tumor biopsy (core, punch, incisional or excisional).
• Biopsy must meet minimal sampling criteria as defined in the Schedule of Study Procedures (Section 5.10, Footnote N).
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Have adequate organ function per protocol. Specimens must be collected within 28 days prior to the start of study intervention.
Criteria for patients with hepatitis B and C:
Screening for hepatitis B and C are required.
For hepatitis B positive patients:
For hepatitis C positive patients:
Patients who are hepatitis C positive (i.e. HCV antibody reactive) or have a history of history of hepatitis C (i.e. history of documented hepatitis C infection) are eligible if they have received and completed hepatitis C directed antiviral therapy at least 4 weeks and have undetectable HCV viral load (HCV RNA) prior to enrollment
Exclusion criteria
Diagnosis of non-cutaneous melanoma histologies including mucosal melanoma, ocular/choroidal melanoma, and acral-lentiginous melanoma.
Prior therapies:
Receipt of prior agent(s) targeting the intestinal microbiome including but not limited to: FMT, defined bacterial consortia, single bacterial species and/or microbiota derived peptides.
Prior chemotherapy, targeted therapy, and/or small molecule therapy within 2 weeks (or 4 half lives) prior to study Day 1.
Prior therapy with lenvatinib or other systemic anti-angiogenic therapy.
Prior radiotherapy within 2 weeks of start of study intervention.
Contraindications to receiving lenvatinib:
• Has had major surgery within 3 weeks prior to first dose of study interventions.
NOTE: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
NOTE: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
• Prolongation of QTcF interval to >480 ms.
NOTE: If the QTcF is prolonged to >480 ms in the presence of a pacemaker, contact the Sponsor to determine eligibility.
• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
NOTE: Medically controlled arrhythmia would be permitted.
Presence of an absolute contraindication(s) to FMT administration
Patients who have not adequately recovered (i.e., ≤Grade 1 or at baseline or ≤Grade 2 endocrinopathy) from adverse events (AEs) due to a previously administered agent
A WOCBP who has a positive urine pregnancy test at Screening (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Has received a live vaccine within 30 days prior to the first dose of study drug.
Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
o Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
Concurrent non-hematologic malignancy within 3 years of data of first planned dose of therapy except for tumors with a negligible risk of metastasis and/or death as defined below:
Adequately treated non-invasive malignancies including but not limited to melanoma in situ (MIS), cutaneous squamous cell carcinoma (cSCC), in situ cSCC, basal cell carcinoma (BCC), CIS of cervix, or DCIS/LCIS of breast.
Low-risk early-stage prostate adenocarcinoma (T1-T2a N0 M0 and Gleason score ≤6 and PSA ≤10 ng/mL) for which the management plan is active surveillance, or prostate adenocarcinoma with biochemical-only recurrence with documented PSA doubling time of > 12 months for which the management plan is active surveillance.
Indolent hematologic malignancies for which the management plan is active surveillance including but not limited to CLL/indolent lymphoma.
Active (i.e., symptomatic or growing) central nervous system (CNS) metastases.
Has severe hypersensitivity (≥Grade 3) to anti-PD(L)1 inhibitor. Has a systemic disease that requires systemic pharmacologic doses of corticosteroids greater than 10 mg daily prednisone (or equivalent).
Has a history of interstitial lung disease or active, non-infectious pneumonitis that required steroids or has current pneumonitis.
Active infections:
Any active infection requiring systemic therapy.
Active TB (Bacillus Tuberculosis).
Active COVID-19 infection and/or exposure to SARS-CoV-2 as defined below:
Active human immunodeficiency virus (HIV) infection.
o Patients will be evaluated for HIV during screening.
Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit through 120 days after the last dose of trial treatment.
Has had an allogenic tissue/solid organ transplant.
Primary purpose
Allocation
Interventional model
Masking
0 participants in 2 patient groups
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Central trial contact
Danielle L Bednarz, RN; Amy Rose, RN
Data sourced from clinicaltrials.gov
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